Project Description Atherosclerotic cardiovascular disease (CVD), the largest killer of men and women in the United States, is closely associated with osteoporosis, another age-associated bone disorder. It has been proposed that there is direct interplay between skeleton and vascular system during aging. However, the cellular and molecular basis for this bone-vascular interaction remains poorly understood. We recently revealed that bone marrow Trap+ pre- osteoclasts (POCs) secrete PDGF-BB, favoring angiogenesis and osteogenesis for bone homeostasis in young mice. Interestingly, we detected much higher levels of PDGF-BB in bone marrow and blood of old mice and rats relative to young animals. After PDGF-BB was deleted in Trap+ POCs in a genetic mouse model, PDGF-BB level in circulating blood of mice was dramatically reduced, indicating that Trap+ POCs in bone is one of the main sources of circulating PDGF-BB. Importantly, age-associated arterial changes including atherosclerotic lesion formation and alteration of aortic wall composition were also dramatically attenuated in old mice after PDGF-BB was deleted in Trap+ POCs. The results suggest a key role of Trap+ cell-derived PDGF-BB in age-associated vascular changes. In addition, we found that bone marrow POCs from old mice (vs. young mice) underwent senescence and secreted much more PDGF-BB, indicating that PDGF-BB may be a factor specifically secreted by senescent POCs. Finally, intermittent parathyroid hormone (iPTH) treatment, a FDA-approved anabolic therapy for osteoporosis, antagonized bone marrow cell senescence, reduced bone marrow and blood PDGF- BB levels, and attenuated atherosclerosis formation in aged mice. Our central hypothesis is that with advancing age, skeletal Trap+ POCs undergo senescence and secrete excessive PDGF-BB into blood circulation, leading to arterial aging; rejuvenation of bone marrow POCs by iPTH decelerates arterial aging. The hypothesis will be tested by the following Specific Aims. Aim 1 will determine the contribution of bone marrow POCs to arterial aging. We will test if deletion of PDGF-BB specifically in Trap+ cells can rescue/attenuate age-associated arterial stiffness and altered vasoreactivity as well as the atherosclerosis formation. Aim 2 will define the senescence of POCs as a mechanism for excessive PDGF-BB production during aging. We will monitor the senescence of bone marrow POCs in old mice. We will then test if selective elimination of the bone marrow senescent cells in old mice will reduce the blood PDGF-BB level. Aim 3 will examine the effects of iPTH as a therapeutic strategy to decelerate arterial aging. As we found that iPTH treatment in old mice eradicated the senescent cells only in bone marrow but not in other tissues, we will first examine if the senescent bone marrow POCs in old mice can be specifically rejuvenated by iPTH treatment. We will also examine if iPTH treatment in old mice can decelerate/attenuate age-associated arterial stiffness and atherosclerosis lesion formation. With this work we hope to develop novel therapies that simultaneously treat both diseases for the elderly population.